PROJECT SUMMARY/ABSTRACT The goal of the proposal is to perform experiments encompassing human brain imaging and human postmortem studies aimed at identifying neuronal markers of treatment response to antipsychotic medication (APD). Our imaging studies have made significant progress by revealing that limbic neuronal networks are related to psychosis and treatment response to APD. In drug-free patients we found psychotic symptoms to be related to rCBF patterns in the anterior cingulate cortex (ACC) and the hippocampus (HIP). APD-induced functional changes in ventral striatum (VS) and HIP observed after one week of treatment are predictive of treatment response. Our postmortem studies of the striatum indicate that patients who responded to treatment had more dopaminergic (DA) synapses, suggesting that elevated striatal DA relates to treatment response. In addition, the number of glutamate (GLU) synapses was significantly different between treatment good (GR) and poor (PR) responders, suggesting that GLU transmission is affected differentially. The results of these studies informed our hypothesis that in GR, DA receptor blockade in VS restores GLU transmission that was inhibited through elevated DA. Consequently, there is greater GLU activity in VS and GLU-mediated projections to limbic regions, such as the ACC and HIP, leading to restored neuronal integrity. We have hypothesized that the early physiological processes that lead to therapeutic benefit with APD are related to changes in GLU transmission within the VS and in GLU-mediated projections to limbic regions and that treatment response in good and poor responders is characterized by differential pattern of alterations affecting the integrity and function of neuronal synapses. We will test this hypothesis using complementary imaging and postmortem yielding data that will permit the formulation of a comprehensive model for APD responses in subjects with severe mental illness. We will seek to replicate and extend our PET findings with fMRI using tasks that are known to activate the HIP (Episodic memory task) and the ACC (Stroop task). This aim will further seek to parse out the differential contribution of the HIP and ACC to treatment response. At the same time, N-acetylaspartate (NAA), a marker of neuronal integrity and GLU measurements obtained with proton magnetic resonance spectroscopy (1H-MRS) will directly probe in the living brain the relation between neuronal integrity, GLU-function and treatment response. In parallel, the postmortem work will concentrate on the ACC, as this region shows the most reliable imaging data. We will attempt to determine the mechanism by which changes in NAA and GLU are made by examining input and output layers of the ACC in GR and PR. We will quantify morphological indicies of neuronal integrity in glutamte neurons, count the number and structural integrity of mitochondria in GLU neurons and count the number and size of glutamatergic synapses.These studies should allow the development of hypotheses about the pathophysiology of treatment response and provide a basis for the interpretation of functional imaging data. The overarching goal is to identify imaging markers that will predict treatment response, and to confirm or validate these biomarkers using anatomical studies of postmortem tissue. Early detection of drug response would yield specific treatment strategies that are tailored to the individual, thus improving both the quality of life of the patients and drastically reducing the costs associated with unsuccessful treatments strategies.